Novel process for the manufacture of pharmaceutical preparations

ABSTRACT

The present invention is related to an improved method for the manufacture of Micro-precipitated Bulk Powder (MBP) containing the active pharmaceutical ingredient Propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3- b ]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide and Hydroxypropylmethylcellulose Acetate Succinate (HPMCAS). The invention is further directed to pharmaceutical compositions containing said MBP, as well as its use in the manufacture of medicaments for the treatment of cancer.

PRIORITY TO RELATED APPLICATION(S)

This application claims the benefit of European Patent Application No.09175665.0, filed Nov. 11, 2009, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention is related to an improved method for themanufacture of solid dispersions, in particular Micro-precipitated BulkPowder (MBP), containing the compound Propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide(formula 1) and Hydroxypropylmethylcellulose Acetate Succinate (HPMCAS).

The compound of formula 1, methods of synthesizing it as well asconventional pharmaceutical formulations containing that compound havebeen disclosed in WO 2007002433 and WO 2007002325. The compound offormula 1 shows valuable pharmaceutical properties as potentialmedicament for the inhibition of cancer proliferation, in particularsolid tumor growth.

BACKGROUND OF THE INVENTION

Compounds that have low solubility in water (for example, certaincompounds in crystalline form), have a low dissolution rate and as aresult can exhibit poor bioavailability. Poorly bioavailable compoundscan present problems for therapeutic administration to a patient, oftendue to unpredictability in dose/therapy effects caused by erraticabsorption of the compound by the patient. For example, the intake offood may affect the ability of the patient to absorb such poorlybioavailable compounds, thus potentially requiring dosing regimens totake into account the effect of food. In addition, when dosing, a largesafety margin may be required for the dose as a result of theunpredictable dose effects. Further, due to poor bioavailability, alarge dose of the compound may be required to achieve a desiredtherapeutic effect, thus potentially resulting in undesired sideeffects.

The amorphous form of Compound 1 has improved solubility in water ascompared to the crystalline form, but is unstable as it has a tendencyto crystallize. Thus it is desired to formulate Compound I so that itmay exist stably primarily in amorphous form.

HPMCAS is a polymer that has been used for the manufacture of soliddispersions (SD) of drugs (see for example H. Konno, L. S. Taylor,Journal of Pharmaceutical Sciences, Vol. 95, No. 12, 2006, 2692-2705).

EP 0 901 786 B1 discloses a composition comprising a spray-dried soliddispersion of a poorly water soluble drug and HPMCAS. Disclosed drugsare glycogen phosphorylase inhibitors and 5-lipoxygenase inhibitors asdisclosed in WO 96/39385 and WO 95/05360 respectively.

EP 1 368 001 B1 discloses a pharmaceutical formulation comprising thedrug bicalutamide and an enteric polymer, like HPMCAS. Disclosed methodsfor evaporating the solvent include rotary evaporation, spray drying,lyophilisation and thin film evaporation. It is further disclosed thatother techniques may be used such as solvent controlled precipitation,pH controlled precipitation, spray congealing and supercritical fluidtechnology (eg, the Solution Enhanced Dispersion by Supercritical Fluid(SEDS) technique).

EP 0 344 603 B1 discloses formulating HPMCAS with a drug designated asNZ-105. The patent discloses formulations prepared by dissolving NZ-105and HPMCAS in an organic solvent and removing the solvent by means ofvacuum-drying, spray-drying, freeze-drying, or the like. Morespecifically, dispersions of HPMCAS and NZ-105 are formed by (1)fluidized bed granulation by coating either calcium hydrogen phosphateparticles or lactose crystals or 2) vacuum drying with lactose to form asolid cake that is then pulverized to form a powdery material. Particlesizes are described to be in the range of 100 to 400 mesh (0.037 mm to0.149 mm).

EP 0 580 860 discloses a process for the preparation of a soliddispersion of drug dissolved in a polymer, which polymer is inter aliaHPMCAS. The claimed process is characterized by the use of a twin-screwextruder being equipped with paddle means.

F. Tanno et. al. disclose the use of HPMCAS as a carrier in soliddispersions. The specific drug used as a model substance in the study isNifedipine. The solid dispersions were obtained by spraying a mixture ofHPMCAS and the drug in an organic solvent on a Teflon™ sheet,evaporating the solvent and removing an milling the resulting film (inDrug Development and Industrial Pharmacy, Vol. 30, No. 1, 2004, 9-17).Molecular Pharmaceutics, Vol. 5, No. 6, 2008, 1003-1019 also disclosesHPMCAS spray-dried dispersions using several poorly water soluble drugs.

Bruno C. Hancock, George Zografi, Journal of Pharmaceutical Sciences,Vol 86, No. 1, 1997, 1-12 discloses methods for removing solvents whenmaking solid dispersions using the so called solvent method, includingfor example spray-drying, vacuum-drying, freeze-drying or precipitation.

SUMMARY OF THE INVENTION

In certain aspects and embodiments there are provided methods ofpreparing solid dispersions comprising HPMCAS and the compound offormula 1. In many embodiments the methods may use a lower amount oforganic solvents as compared to other methods and as such may be moreenvironmentally friendly; are safe when used on an industrial scale;and/or show improved properties such as stability againstre-crystallization. In many aspects and embodiments the methods involvemicro-precipitation of a mixture of HPMCAS and the compound of formula 1within an aqueous phase using the conditions and process parameters asdescribed herein.

In one embodiment there is provided a method for manufacturing a soliddispersion containing the amorphous form of the compound of formula 1and HPMCAS, wherein the solid dispersion is obtained by introducing asolution of the compound of formula 1 and HPMCAS in the same organicsolvent within an aqueous phase, and subsequent precipitation andisolation of said solid dispersion from said aqueous phase.

In certain more specific embodiments, the above method includes thefollowing steps,

(a) dissolving the compound of formula 1 and HPMCAS in the same organicsolvent to give one single organic phase;(b) continuously adding the organic phase obtained under (a) into anaqueous phase which is present in a mixing chamber, said mixing chamberbeing equipped with a high shear mixing unit and two additional openingswhich connect said mixing chamber to a closed loop wherein said aqueousphase is circulated and passes through the mixing chamber;(c) precipitating a mixture consisting of the amorphous form of thecompound of formula 1 and HPMCAS out of the aqueous phase mentionedunder (b), while the high shear mixer is operating and said aqueousphase is passed through the mixing chamber in a closed loop, resultingin the formation of an aqueous suspension of the precipitate;(d) continuously circulating the aqueous suspension through the mixingchamber while the high shear mixing unit is operating and after theorganic solution prepared under (a) has been completely added to theaqueous phase until a defined particle size and/or particle sizedistribution is obtained;(e) isolating the solid phase from the suspension;(f) washing of the isolated solid phase with 0.01 N HCl and/or water;and(g) delumping and drying the solid phase.

In still more specific embodiments the present methods include thesteps, wherein

-   -   the organic phase in step (a) above is a 10 to 40% solution of        the compound of formula 1 and HPMCAS in DMA, the ratio of said        compound to HPMCAS being from about 10 to 90% (w/w) to about 60        to 40% (w/w); and    -   the continuous adding in step (b) above is achieved via an        injector nozzle which is oriented in an angle between 40 and 50°        to the longitudinal axis of the high shear mixer and has a        distance of about 1 to about 10 mm from the rotor of said high        shear mixer which is operating with a tip speed of about 15 to        about 25 m/sec.

In still more specific embodiments the present methods include the step,wherein

-   -   the continuous adding in step (b) above is achieved via an        injector nozzle which is oriented in an angle of about 45° to        the longitudinal axis of the high shear mixer and has a distance        of about 2 to about 4 mm from the rotor of said high shear mixer        which is operating with a tip speed of about 25 m/sec.

In other specific embodiments the present methods include the step,wherein

-   -   the drying in step (g) above is achieved via fluidized bed        drying.

In yet another particularly preferred embodiment, the organic phase in(a) comprises DMA, the compound of formula 1 and HPMCAS-L, and step (b)comprises adding said organic phase into aqueous (0.01 N) HCl at a massflow ratio in the range of about 80/1 to 200/1 (aqueous phase/organicphase) while said aqueous HCl is kept at a temperature of about 2-8° C.

In a further embodiment there are provided the solid dispersionsobtained by the above-mentioned method.

The dried precipitate can be further processed into any type of solidpharmaceutical preparations or dosage forms, which are known to theperson of skill in the art. Particularly preferred are oral dosage formssuch as tablets, capsules, pills, powders, suspensions, pasts and thelike. Detailed descriptions of suitable excipients as well as methodsfor making such pharmaceutical preparations can for example be found in:Raymond C. Rowe et al, Handbook of Pharmaceutical Excipients, 6^(th)edition, 2009, Pharmaceutical Press (Publ.); ISBN-10: 0853697922.

Consequently, so obtained pharmaceutical preparations form furtherembodiments provided herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a schematic drawing of the setup for the manufacturing ofsolid dispersion (MBP) according to the present invention. The setupprovides two reservoirs (vessels) with temperature control means, onefor providing the aqueous phase at a controlled temperature (1), theother for providing the organic phase at a controlled temperature (2).Both vessels are further equipped with automatic stirrers (3). Theaqueous phase is circulated in a closed loop (4) using a pump (5), whilepassing a high shear mixing unit (6). The organic phase is added intothe aqueous phase within the high shear mixing unit with the aid of adosing pump (7) and via an injector nozzle which is shown in more detailin FIG. 2.

FIG. 2 shows are more detailed schematic drawing of the high shearmixing unit ((6) of FIG. 1). The nozzle (8) is placed within the aqueousphase inside the high shear mixing unit. The nozzle can be orientedwithin different angles (α) with respect to the rotor (9) of the highshear mixing unit, and within defined distances (d) of the rotor tip.

FIG. 3 shows the comparison of X-ray diffractograms obtained from twolots of solid dispersions (MBP's), manufactured via high shear mixerprecipitation according to the present invention (3 a) and viaconventional spray precipitation (3 b). The results presented in thisfigure demonstrate that the spray precipitated MBP is less stableagainst re-crystallization than the high shear precipitated MBP asevidenced by the early occurrence of sharp signals in the diffractogramsof (b), which can be allocated to the crystalline form of the compoundof formula (1). Bottom line in each picture represents the initialsample, the following lines bottom up after 14 h, 41 h, 96 h, 6 drespective 13 d storage in a clime chamber (50° C. 90% RH).

DETAILED DESCRIPTION OF THE INVENTION

The compound of formula 1, which is an active pharmaceutical ingredient(API), and the excipient Hydroxypropylmethylcellulose Acetate Succinate(HPMCAS) is dissolved in an organic, water miscible solvent in a feedhopper. In a second vessel an aqueous phase of defined temperature ispumped in a loop outside of the vessel, while passing through a highshear mixer (HSM, rotor/stator unit). A schematic drawing of the processcan be seen in FIG. 1. The temperature of both solutions was controlledduring the complete manufacturing process. The solution with the API andexcipient (organic phase) is dosed with a defined flow rate into themixing chamber, containing the rotor/stator tools, while the high shearunit (dispersing unit) is operating. During the mixing of the twoliquids (aqueous- and organic phase) an almost water insolubleprecipitate, which is a mixture of amorphous API and HPMCAS with adefined ratio, is formed, leading to a suspension of micro precipitatedbulk powder (MBP) in the outer phase (mixture of water and organicsolvent). After complete addition of the organic phase the suspensionwas forced a number of passes through the dispersing unit in order toadjust the particle size. Subsequently the suspension was centrifugedand washed with a water phase several times in order to remove theorganic solvent and finally was washed additionally with pure water. Theobtained wet MBP was delumped and dried to a water content below 2% byweight (w/w). The MBP was obtained as a white, free flowing powder.

The compound of formula 1 can be synthesized according to methodsdisclosed in WO 2007002433 or WO 2007002325.

The term “HPMCAS” means Hydroxypropylmethylcellulose Acetate Succinate(trade name: AQOAT, available from Shin-Etsu Chemical Industry Co.,Ltd., Japan or appointed distributors), which is available in thefollowing grades: AS-LF, AS-MF, AS-HF, AS-LG, AS-MG and AS-HG. Thesolubility of the different HPMCAS grades as well as their drug releasebehaviour depends on the pH-value of the environment. Accordingly, therelease behaviour of a drug can be tailored in the range of about pH5.2to about pH6.5 by the choice of the appropriate HPMCAS grade (seeproduct information brochure for AQOAT). Therefore, in one embodiment,the compound of formula 1 is in a solid dispersion with at least onepolymer selected from HPMCAS grades AS-L, AS-M, AS-H. It is, however,contemplated that a mixture of two or more of the various HPMCAS gradescan also be used in accordance with the present invention.

The term “solid dispersion” as used herein means a solid state materialformed by a high molecular weight compound, such as a polymer,preferably HPMCAS, wherein a low molecular weight compound, such as thecompound of formula 1, is molecularly dispersed. Preferably the soliddispersion exists as a one phase system. An especially preferred soliddispersion according to the present invention is a microprecipitatedbulk powder (MBP) essentially consisting of HPMCAS and the compound offormula 1 which is predominantly in its amorphous form.

The “organic solvent” mentioned under step (a) means any organic solventwherein both the compound of formula 1 and HPMCAS are miscible.Preferred organic solvents are N-Methylpyrrolidone, Dimethylformamide,Dimethylsulfoxide, Dimethylacetamide (DMA), with DMA being the mostpreferred. The combined amount of the compound of formula 1 and HPMCAStogether in the organic phase can be within the range of about 10 to 40weight %, preferably about 15 to 40 weight %, more preferably about 25to 40, most preferably about 35 weight %. The weight ratio of thecompound of formula 1/HPMCAS within the organic solvent is from about10/90 to about 60/40 weight %, more preferably from about 30/70 to about60/40 weight %, and most preferably about 30/70 weight %, respectively.Preferably, the temperature of the organic solvent is adjusted between50 and 110° C., preferably 60 and 90° C., most preferred at about 70° C.prior to its addition to the mixing chamber as mentioned under step (b).The mixture of the compound of formula 1 and HPMCAS in the organicsolvent is also designated herein as the “organic phase” or “DMA phase”.

The “aqueous phase” mentioned under step (b) preferably consists ofacidic water (pH<7), most preferably of 0.01 N hydrochloric acid (HCl).The aqueous phase is kept at a temperature between about 2 and about 60°C., preferably between about 5 and about 20° C., most preferably about5° C. The aqueous phase circulates out of the bottom valve of itsreservoir ((1) of FIG. 1) due to the stream created by the high shearmixer or with an auxiliary pump, preferably a rotary lobe pump, thenpasses through the high shear mixer, back into the reservoir.Preferably, the outlet of the loop is placed under the fluid levelmaintained in the reservoir, in order to prevent foaming.

The addition of the organic phase to the mixing chamber as mentioned instep (b) above is achieved via an injector nozzle which directly pointsinto the aqueous phase. Any conventional nozzle known to the person ofskill in the art can be used. Preferred injector nozzles show central oracentric geometry are isolated and have a diameter of about 1 to 10 mm.The acentric (not centered) geometry and a diameter of 5 mm areespecially preferred. The injector nozzle may point to the rotor of thehigh shear mixing unit in an angle between 0 and 90°, preferably between40 and 50°, most preferably at 45° (α, FIG. 2). During the processaccording to the present invention, the distance between the point ofthe injector nozzle and the tip of the rotor of the high shear mixingunit is about 1 to 10 mm, preferably about 2 to 4 mm and most preferablyabout 2.6 mm. The addition of the organic phase is preferably carriedout at dosing rates of about 60/1 to about 300/1 (i.e. mass flow ratioof aqueous phase/organic phase during precipitation), preferably about70/1 to about 120/1 and most preferably at about 100/1. Final ratio ofaqueous phase/organic phase after precipitation is in the range of about5/1-12/1 preferably 7/1-10/1 and most preferably at 8.5/1.

While the organic phase is added (injected) into the aqueous phase ofthe mixing chamber, the high shear mixing unit is operating. Anyconventional high shear mixing unit (rotor/stator unit) known to theperson of skill in the art can be applied. Especially preferred aretoothed disk dispersing units. The preferred rotor geometry according tothe present invention uses a rotor/stator unit with a radial singleteeth row or double teeth row or combination thereof. Rotors withconical teeth rows can also be applied. The tip speed of the rotor isfrom about 15 to about 25 m/sec., preferably 25 m/sec.

Subsequent to the complete addition of the organic phase into theaqueous phase, the obtained suspension, thus the precipitate consistingof the amorphous compound of formula 1 and HPMCAS in the aqueous phase,is further circulated in the closed loop containing the high shearmixing unit. Outside of the high shear mixing unit the circulation mustbe carried out with the aid of an auxiliary pump, preferred a rotarylobe pump. The suspension passes the high shear mixing unit severaltimes, up to the moment where a desired particle size and/or particlesize distribution is obtained. Usually the suspension passes the highshear mixing unit about 1 to 60 times, most preferably 6 times. Theparticle size and/or particle size distribution can be controlled bystandard techniques, well known to the person of skill in the art, suchas for example dynamic light scattering. The preferred particle sizeaccording to the present invention is with in the range of D50=80-230 μmpreferably D50=80-160 μm.

Isolation of the solid dispersion (MBP) according to step (e) above canbe carried out by using conventional filter techniques or centrifuges.Prior to isolation, the suspension is preferably adjusted to about 5 to10° C. Subsequently, the isolated solid dispersion is washed with acidicwater; preferably 0.01 N HCl followed by further washing with pure waterin order to substantially remove the organic solvent (step (f)). Theisolated (wet) solid dispersion (MBP) usually shows a water contentbetween 60 and 70% (w/w), which requires drying before any furtherprocessing. The drying can be carried out using any standard techniquesknown to the person of skill in the art, for example using a cabinetdryer at temperatures between 30 and 50° C., preferably at about 40° C.and at reduced pressure, preferably below 20 mbar. Several dryingprocedures can be combined or used sequentially, whereby the use offluidized bed drying is especially preferred as the final drying stepaccording to the present invention.

The stability of the solid dispersion (MBP) according to the presentinvention was compared with the stability of an MBP obtained viaconventional spray precipitation. “Conventional spray precipitation”means that the organic phase was sprayed onto the aqueous phase via anozzle which is placed outside the aqueous phase, above its surface likeit is the case for many conventional spray-precipitation techniques. Allfurther process parameters are the same for both methods. The stability,thus the inhibition of re-crystallization of the compound of formula 1,is determined by x-ray diffraction measurements, using a conventionalwide angle X-ray scattering setup as it is well known to the skilledartisan. Sample preparation was identical for both MBP's. The sampleswere treated in a climate chamber (50° C. and 90% humidity (RH)) forseveral hours respective days (0 h, 14 h, 41 h, 4 d, 6 d, 13 d) prior toX-ray measurements. The results are shown in FIG. 3 (a) for the MBPobtained according to the present invention, and (b) for the MBPobtained by the conventional method. The earliest X-ray curves of bothMBP's show a broad halo in the wide angle region with the absence ofsharp signals, thereby clearly evidencing that both materials are in anamorphous state. Within several days, sharp signals occur in the X-raycurves obtained from the MBP manufactured by the conventional method((b) in FIG. 3), but not in the X-ray curves obtained from the MBPprepared using the method as disclosed herein ((a) in FIG. 3).

The novel processes as provided herein can preferably be carried outusing a setup as shown in the accompanying FIG. 1.

The solid dispersion, in particular the MBP obtainable according to themethods provided can be used in a wide variety of forms foradministration of drugs such as the compound of formula 1, includingdrugs that are poorly water soluble, and in particular for oral dosageforms. Exemplary dosage forms include powders or granules that can betaken orally either dry or reconstituted by addition of water to form apaste, slurry, suspension or solution; tablets, capsules, or pills.Various additives can be mixed, ground or granulated with the soliddispersion as described herein to form a material suitable for the abovedosage forms. Potentially beneficial additives may fall generally intothe following classes: other matrix materials or diluents, surfaceactive agents, drug complexing agents or solubilizers, fillers,disintegrants, binders, lubricants, and pH modifiers (e.g., acids,bases, or buffers). Examples of other matrix materials, fillers, ordiluents include lactose, mannitol, xylitol, microcrystalline cellulose,calcium diphosphate, and starch. Examples of surface active agentsinclude sodium lauryl sulfate and polysorbate 80. Examples of drugcomplexing agents or solubilizers include the polyethylene glycols,caffeine, xanthene, gentisic acid and cyclodextrins. Examples ofdisintegrants include sodium starch gycolate, sodium alginate,carboxymethyl cellulose sodium, methyl cellulose, and croscarmellosesodium. Examples of binders include methyl cellulose, microcrystallinecellulose, starch, and gums such as guar gum, and tragacanth. Examplesof lubricants include magnesium stearate and calcium stearate. Examplesof pH modifiers include acids such as citric acid, acetic acid, ascorbicacid, lactic acid, aspartic acid, succinic acid, phosphoric acid, andthe like; bases such as sodium acetate, potassium acetate, calciumoxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calciumhydroxide, aluminum hydroxide, and the like, and buffers generallycomprising mixtures of acids and the salts of said acids. At least onefunction of inclusion of such pH modifiers is to control the dissolutionrate of the drug, matrix polymer, or both, thereby controlling the localdrug concentration during dissolution.

As was stated earlier, additives may be incorporated into the solidamorphous dispersion during or after its formation. In addition to theabove additives or excipients, use of any conventional materials andprocedures for formulation and preparation of oral dosage forms usingthe compositions disclosed herein known by those skilled in the art arepotentially useful.

Consequently, a further embodiment includes a pharmaceutical preparationcontaining the solid dispersion as obtained by a method as describedherein. The preparation may optionally also contain additionalpharmaceutically acceptable adjuvants.

In one embodiment, the solid dispersion may be processed into afilm-coated tablet containing up to 92% of the MBP obtainable accordingto the process disclosed herein, and wherein the MBP consists of about30% compound of formula (1) and about 70% HPMCAS. The remaining part ofthe tablet consists of a mixture of conventional disintegrants such asfor example croscarmellose sodium; glidant such as for example colloidalanhydrous silica; binders such as for example hydroxypropylcellulose;lubricants such as for example Magnesium stearate; and a film coat. Anyconventional film coating mixture known to the skilled person can beapplied, e.g. Opadry II pink 85F14411. A representative mixture for afilm-coated tablet is given in Example 6.

In still another embodiment, there is provided a solid dispersion asobtained according to the present process for use as a medicament.

In yet another embodiment there is provided the use of the soliddispersion obtainable by the present process in the manufacture ofmedicaments for the treatment of cancer, in particular solid tumors, andmore particularly malignant melanomas.

In still another embodiment, there is provided the solid dispersion asobtained according to the present process for use as a medicament forthe treatment of cancer, in particular solid tumors, and moreparticularly malignant (metastatic) melanoma.

EXAMPLES

The invention will become apparent by the following examples which aregiven for illustration of the invention rather than limiting itsintended scope.

Example 1 Preparation of the DMA Phase

The concentration of the compound of formula 1 and HPMCAS in the organicsolvent was 35% (w/w), while the ratio of the compound of formula 1 andHPMCAS is 30 to 70: The temperature of the solution was adjusted to 70°C.

In a 250 ml double jacked glass flask reactor 21 g of the compound offormula 1 were dissolved in 130 g Dimethylacetamide (DMA) at 20-25° C.Under stirring, 48.9 g of HPMC-AS were added to the solution. Themixture was heated up to 70° C. A clear solution was obtained.

Example 2 Preparation of the Aqueous Phase

In a double jacketed 2.0 liter reactor 1210 g of 0.01 N HCl was temperedto 5° C. Out of the bottom valve of the reactor the water phase wascirculated by the high shear mixer or with an auxiliary pump, preferreda rotary lobe pump, and then followed by the high shear mixer, back tothe top of the reactor. The inlet of the recirculation into the reactorwas under the fluid level in order to prevent foaming (see FIG. 1).

Example 3 Precipitation High Shear Mixer

The tip speed of the rotor in the high shear mixer was set 25 m/sec. Arotor/stator combination with one teeth row, each for rotor and statorwas used.

Dosing of the DMA Solution

The DMA solution tempered at 70° C. was dosed with a gear pump via aninjector nozzle, which was pointing into the mixing chamber of the highshear mixer, into the circulating aqueous phase.

Dosing Rate of the DMA Solution

The DMA solution was dosed into the aqueous phase resulting in a ratioof HCl/DMA, in the mixing chamber of the high shear mixer of 100/1.

Example 4 Additional Dispersing in the HSM (after Precipitation),Isolation and Washing

After addition of the DMA solution the obtained MBP suspension wasdispersed for an additional time, corresponding to equivalents of thebatch passing the high shear mixer. The time was corresponding to aturnover in calculated recirculation times of the batch of 6 times. Theobtained suspension, hold at 5-10° C. was separated from the solid MBP.This was be done by using a suction filter. The isolated MBP was washedwith 0.01 N HCl (15 kg 0.01 N HCl/kg MBP) followed by a washing withwater (5 kg water/kg MBP) in order to remove the DMA. The isolated (wet)MBP had a water content between 60 and 70%.

Example 5 Delumping and Drying

Prior to drying the (wet) MBP was delumped by using a sieve mill. The(wet) MBP was dried in a cabinet dryer. During the drying process of theMBP the temperature of the product was below 40° C. in order to avoidrecrystallization of the API. The pressure inside the cabinet dryer wasbelow 20 mbar. The water content of the MBP after drying was below 2.0%and was signed amorphous in the XRPD pattern.

Example 6 Film Coated Tablet

Component Quantity (mg/tablet) MBP (30% compound (1), 800.00 70% HPMCAS)Croscarmellose sodium 29.40 Colloidal anhydrous silica 10.40Hydroxypropylcellulose 4.25 Magnesium stearate 5.95

The above mentioned ingredients were mixed and pressed into tablets byconventional means. The film coat consists of Poly(vinyl alcohol) (8.00mg), Titanium dioxide (4.98 mg), Macrogol 3350 (4.04 mg), Talc (2.96 mg)and Iron oxide red (0.02 mg). Any other conventional film coat mixture,like e.g. Opadry II pink 85F14411, may also be used.

1. A method for manufacturing a solid dispersion containing the amorphous form of the compound of formula 1

and HPMCAS, comprising the following steps: (a) dissolving the compound of formula 1 and HPMCAS in the same organic solvent to give one single organic phase; (b) continuously adding the organic phase obtained under (a) into an aqueous phase which is present in a mixing chamber, said mixing chamber being equipped with a high shear mixing unit and two additional openings which connect said mixing chamber to a closed loop wherein said aqueous phase is circulated and passes through the mixing chamber; (c) precipitating a mixture consisting of the amorphous form of the compound of formula 1 and HPMCAS out of the aqueous phase mentioned under (b), while the high shear mixer is operating and said aqueous phase is passed through the mixing chamber in a closed loop, resulting in the formation of an aqueous suspension of the precipitate; (d) continuously circulating the aqueous suspension through the mixing chamber while the high shear mixing unit is operating and after the organic solution prepared under (a) has been completely added to the aqueous phase until a defined particle size and/or particle size distribution is obtained; (e) isolating the solid phase from the suspension; (f) washing of the isolated solid phase with 0.01 N HCl and/or water; and (g) delumping and drying the solid phase.
 2. The method according to claim 1, wherein the organic phase in (a) is a 10 to 40% solution of the compound of formula 1 and HPMCAS in DMA, the ratio of said compound to HPMCAS being from about 10 to 90% (w/w) to about 60 to 40% (w/w); and the continuous adding in step (b) is achieved via an injector nozzle which is oriented in an angle between 40 and 50° to the longitudinal axis of the high shear mixer and has a distance of about 1 to about 10 mm from the rotor of said high shear mixer which is operating with a tip speed of about 15 to about 25 m/sec.
 3. The method according to claim 2, wherein the organic phase in (a) is a 35% solution of the compound of formula 1 and HPMCAS in DMA, the ratio of said compound to HPMCAS being 30% to 70% (w/w).
 4. The method according to claim 1, wherein the organic phase in (a) comprises DMA, the compound of formula 1 and HPMCAS-L, and step (b) comprises adding said organic phase into aqueous (0.01 N) HCl at a mass flow ratio in the range of about 80/1 to 200/1 (aqueous phase/organic phase) while said aqueous HCl is kept at a temperature of about 2-8° C.
 5. The solid dispersion produced by the method according to claim
 1. 6. The solid dispersion according to claim 5, characterized in that it is a microprecipitated bulk powder (MBP) wherein the compound of formula 1 is predominantly present in its amorphous form.
 7. A pharmaceutical preparation containing the solid dispersion as obtainable according to the method of claim 1, optionally together with additional pharmaceutically acceptable adjuvants. 